Almost $19bn was added to Lilly’s market cap when donanemab met the primary endpoint of Trailblazer-Alz back in January. It will become clearer whether the Alzheimer’s disease project is worthy of the excitement when full results from the trial are presented on March 13 at the medical conference AD/PD 2021.
Lilly has already said that not all secondary endpoints met statistical significance, but this might not matter too much if a consistent benefit is shown across the various measures employed. Investors will also be trying to figure out if donanemab could be filed for approval on the back of the phase II trial, though for now only the most bullish will be betting on this outcome.
Lilly is largely responsible for these high hopes. The FDA’s thoughts on early access to donanemab will be sought, according to executives, who have made notably upbeat comments about the impending data. But the dominant opinion seems to be that regulators will want the findings confirmed in Trailblazer-Alz2, a larger ongoing study that is due to read out in 2023.
Whether consensus shifts towards Lilly’s bull case depends on the data.
The phase II Trailblazer-Alz trial enrolled 272 subjects with mild Alzheimer’s, with recruitment restricted to those with low to medium Tau levels. This biomarker-driven design is thought to have played an important role in the study’s success: patients with high Tau levels typically display more rapid cognitive decline, and this subgroup has been blamed for the failure of previous Alzheimer’s trials.
The primary endpoint was iARDS, a composite assessment that combines two cognitive and functional measures, ADAS-Cog13 and ADCSiADL. Donanemab slowed clinical decline on iARDS by a statistically significant 32% relative to control, Lilly disclosed in January (Lilly boosts biopharma with an early Alzheimer’s signal, January 11, 2021).
A big unknown is the absolute difference on iARDS between the two arms. Alzheimer’s experts interviewed by Mizuho analysts reckon a difference of at least three points over placebo would be clinically meaningful; many will hope for a larger number.
The secondary endpoint CDR-SB will be another huge focus, since this a more widely used dementia rating scale in Alzheimer’s trials. A miss cannot be ruled out, if only because it seems likely that Lilly would have already disclosed a win here. It is also important to know that in some previous Alzheimer’s studies iARDS and CDR-SB have generated very different effect sizes in the same patient group.
If CDR-SB does fall short, the extent of the miss will be crucial. For the results to be judged clinically meaningful, Mizuho’s experts need to see at least a one-point difference over placebo. Evercore ISI analysts say that an effect size in the mid-20% range, at the very least, needs to emerge.
Comparisons against other Alzheimer’s trials will inevitably be made, albeit with the usual caveats. For example, on CDR-SB Biogen claimed a 22% relative reduction versus placebo for high-dose aducanumab in the Emerge study; the difference between the two arms was -0.39 points, in favour of the active arm.
Eyes will also be on safety. Lilly has said that 6% of patients suffered symptomatic Aria-E, a brain swelling condition that is frequently seen with beta-amyloid-targeting MAbs. Dropouts have not been disclosed, and are something to watch – in aducanumab trials Biogen lost 8-10% of patients owing to this toxicity.
Assuming no new safety concerns and some convincing statistical hits beyond iADRS, big hopes for donanemab will start to build. Alzheimer’s is better known for disappointments, however, and it should also be considered what a bad result might look like.
Several other measures of cognition and function will be reported, and it would be concerning if they did not all move convincingly in the same direction as iARDS. Biomarkers must also correlate with the effects seen.
A poorly received dataset would raise concerns beyond Lilly and donanemab. As Bernstein analysts put it, if the rest of the data fail to support the primary endpoint, investors will be reminded that there are still big questions over whether beta-amyloid is the right target in Alzheimer’s.